Gene makes muscles in the obese store more fat

DURHAM, N.C. - The gene encoding an enzyme that hinders muscle from burning fat manufactures three times more enzyme in the muscle of obese people than lean people, researchers from Duke University Medical Center and Louisiana State University have found. This causes the obese muscle tissue to both store more fat and burn less fat, the researchers said.

"Obesity is a very complex disease, and this metabolic pathway does not fully explain obesity, but it is a likely contributor," said Deborah Muoio, Ph.D., senior study author and assistant professor of medicine at Duke's Sarah W. Stedman Nutrition and Metabolism Center.

Excess fat storage in muscle tissue is a hallmark of obesity, and may contribute to problems such as diabetes and cardiovascular disease. The researchers discovered that skeletal muscle tissue and cells from obese people were programmed to store fat even when removed from the body and forced to grow in the laboratory. This finding suggests the gene is more active in obese people not only because of excess calorie intake, but also as a result of heritable changes in its regulation, Muoio said.

"The cells of obese people remembered their metabolic program, which could help explain, in part, why losing weight and maintaining weight loss is so difficult," Muoio said. "The good news is it's possible to change your energy balance through exercise. Exercise can enhance muscle's ability to burn fat," Muoio said. "This discovery also provides a potential drug target."

The results appear in the Oct. 12, 2005 issue of Cell Metabolism. The work was supported by National Institute of Diabetes & Digestive & Kidney Diseases, of the National Institutes of Health, the Pennington Biomedical Research Foundation and the American Diabetes Association.

Muoio suspects that the gene's behavior is altered in obese people because of epigenetic control - alteration of gene activity states without variations in the DNA code. These changes can be triggered by environmental factors, such as nutrition or chemical exposure, and carried forward even after the stimulus is removed. The gene investigated in the study is present in obese and lean people, but was overexpressed, or more active, in obese muscle tissue and cells, which means the obese tissue produced larger quantities of enzyme.

In their study, the researchers analyzed stomach muscle tissue donated by non-diabetic obese and lean people who were having surgery. They examined muscle tissue and muscle satellite cells, which have the potential to develop into muscle. Both the tissue and cells from obese people were programmed to store excess fat in the form of fat droplets. The cells and tissue also burned less fat because they produced more of an enzyme that opposes fat oxidation. This excess fat storage may be linked to type 2 diabetes because skeletal muscle - muscle attached to bone - helps regulate sugar metabolism.

When the muscle satellite cells were encouraged to develop into mature muscle cells, they showed the same fat storage programming as muscle tissue. "This is a very important clue, because it indicates this program of fat storage is perpetuated as these cells divide. It's not driven strictly by over-nutrition," Muoio said.

To identify the gene controlling this fat storage pathway, the research team relied on DNA microarrays, or "gene chips," to test the activity of thousands of genes at once. They also selected a few candidate genes (they chose culprits based on earlier research) to examine by a different method. In both cases, they arrived at the same gene, called steroyl-CoA desaturase 1 (SCD1), which was known to slow down fat burning and promotes fat storage.

"We found that obesity was associated with a threefold increase in SCD1 expression in obese muscle, as well as a threefold higher level of SCD1 enzyme, compared to lean muscle," Muoio said. The activity of other genes linked to fat metabolism and obesity were comparable between the two groups.

The researchers also investigated how muscle cells from lean individuals behaved when forced to overproduce the SCD1 enzyme. Using genetic engineering techniques, the team showed that cells from lean people mimicked the metabolism of obese cells, storing more fat droplets and burning less fat, when the amount of SCD1 was increased.

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Contributors include Matthew Hulver and Michael Carper, Pennington Biomedical Research Center, Louisiana State University; Jason Berggren, John Thyfault, G. Lynis Dohm and Joseph Houmard, East Carolina University; Makoto Miyazaki and James Ntambi, University of Wisconsin, Madison; and Eric Hoffman, Children's National Medical Center.

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